心血管外科杂志(电子版) 2016年6月,5卷2期

综述

肺动脉高压药物治疗的研究进展

常忠路 毕研文

453400 河南新乡,河南宏力医院心外科(常忠路);山东大学齐鲁医院心外科(毕研文)
毕研文,Email: yanwenbi1@126.com

摘要:肺动脉高压(PAH)是一种以肺动脉压力和肺血管阻力进行性升高为特征的慢性进展性疾病,最终导致右心衰竭和死亡。本文对PAH 从非特异性血管扩张药物治疗到新型靶向性药物治疗及药物联合治疗作一综述。

关键词:高血压,肺性; 药物治疗; 联合治疗

参考文献

[1] Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll

Cardiol, 2013, 62: D34-41.
[2] Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern

treatment era. Chest, 2011, 140: 301-309.
[3] Thenappan T, Shah SJ, Rich S, et al. Contemporary survival in patients with pulmonary arterial hypertension: a

reappraisal of the NIH risk stratification equation. Eur Respir J, 2010, 35: 1079-1087.
[4] Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary

arterial hypertension from REVEAL. Chest, 2012, 142: 448-456.
[5] Li RC, Cindrova-Davies T, Skepper JN, et al. Prostacyclin induces apoptosis of vascular smooth muscle cells by a

cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of

endothelin-1 or basic fibroblast growth factor. Circ Res, 2004, 94: 759-767.
[6] Badesch DB, Tapson VF, Mcgoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the

scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med, 2000, 132: 425-434.
[7] Mclaughlin VV, Benzal, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial

hypertension: a randomized controlled clinical trial. J Am Coll Cardiol, 2010, 55: 1915-1922.
[8] Ikeda D, Tsujino I, Sakaue S, et a1. Pilot study of short-term effects of a novel long-acting oral beraprost in

patients with pulmonary arterial hypertension. Circ J, 2007, 71: 1829-l831.
[9] Kunieda T, Nakanishi N, Matsubara H, et al. Effects of long-acting beraprost sodium(TRK-100STP) in Japanese patients

with pulmonary arterial hypertension. Int Heart J, 2009, 50: 513-529.
[10] Behza RL, Seeger W, Mclaughlin W, et al. Long-term effects of inhaled treprostinil in patients with pulmonary

arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension(TRIUMPH)

study open-label extension. Heart Lung Transplant, 2011, 30: 1327-1333.
[11] Simonneeau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue,

in patients with pulmonary arterial hypertension: a double-blind randomized, placebo-controlled trial. Am J Respir Crit Care

Med, 2002, 165: 800-804.
[12] Kuwano K, Hashino A, Neda K, et al. A long-acting and highly selective prostaeyelin receptor agonist pro-drug, 2-{4

-[(5, 6-diphenylpyrazin-2-y1) (isoprepyl) amino] butoxy}-N- (methylsulfonyl) acetamide(NS-304), ameliorates rat pulmonary

hypertension with unique relaxant responses of its active form, MRE269, on ratpulmonary artery. Pharmacol Exp Ther, 2008,

326: 691-699.
[13] Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med,

2015, 373: 2522-2533.
[14] Rubin LJ. Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci, 2012, 91:

517-521.
[15] Langleben D. Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Clin Chest Med,

2007, 28: 117-125.
[16] Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertention

with bosentan(EARLY STUDY): a double blind, randomized controlled trial. Lancet, 2008, 371: 2093-2100.
[17] Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertention. Orphanet J Rare Dis, 2013, 8: 97.
[18] Opitz CF, Ewert R, Kirch W, et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial

hypertension: does selectivity matter? Eur Heart J, 2008, 29: 1936-1948.
[19] Seferian A, Simonneau G. Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow?

Eur Respir Rev, 2013, 22: 217-226.
[20] Oudiz RJ, Galiè N, Olschewski H, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial

hypertension. J Am Coll Cardiol, 2009, 54: 1971-1981.
[21] Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of

the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy

(ARIES) study 1 and 2. Circulation, 2008, 117: 3010-3019.
[22] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial

hypertension. N Engl J Med, 2013, 369: 809-818.
[23] Channick RN, Delcroix M, Ghofrani HA, et al. Effect of macitentan on hospitalizations: results from the SERAPHIN

trial. JACC Heart Fail, 2015, 3:1-8.
[24] Galie N, Hoeper MM, Simon J, et al. Liver toxicity of sitaxentan in pulmonary arterial hypertension. Eur Heart J,

2011, 32: 386-387.
[25] Buckley MS, Staib RL, Wicks LM, et al. Phesphediesterase-5 inhibitors in management of pulmonary hypertension:

safety, tolcrahility, and efficacy. Drug Health Patient Saf, 2010, 2: 151-161.
[26] Hoette S, Jardim C, Souza Rd. Diagnosis and treatment of pulmonary hypertension: an update. J Bras Pneumol, 2010,

36: 795-811.
[27] Wang L, Zhang J, Fu W, et al. Association of smooth musclecell phenotypes with extracellular matrix disorders in

thoracic aortic dissection. Vasc Surg, 2012, 56: 1698-1709.
[28] Zhang ZN, Jiang X, Zhang R, et al. Oral sildenafil treatment for eisenmenger syndrome: a prospective, open-label,

multicentre study. Heart, 2011, 97: 1876-1881.
[29] Oudiz RJ, Brundage BH, Galie N, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind

52-week uncontrolled extension study. J Am Coll Cardiol, 2012, 60: 768-774.
[30] 龚霄雷, 朱丽敏, 蔡小满, 等. 伐地那非治疗先天性心脏病术后PAH的疗效观察. 上海交通大学学报: 医学版, 2011, 31: 1287-

1290.
[31] Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-

controlled study. Am J Respir Crit Care Med, 2011, 183: 1723-1729.
[32] Park JS, Lim HJ, Cho YJ, et al. Udenafil improves exercise capacity in patients with chronic obstructive pulmonary

disease: a prospective study. COPD, 2012, 9: 499-504.
[33] Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol, 2013,

218: 279-313.
[34] Geschka S, Kretschmer A, Sharkovska Y, et al. Soluble guanylate cyclase stimulation prevents fibrotic tissue

remodeling and improves survival in salt-sensitive Dahl rats. PLoS One, 2011, 6: e21853.
[35] Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary

disease. Circulation, 2011, 123: 2263-2273.
[36] Rubin LJ, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term

extension study(PATENT-2). Eur Respir J, 2015; 45: 1303-1313.
[37] Fujita H, Fukumoto Y, Saji K, et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor,

in patients with pulmonary arterial hypertehsion. Heart Vessels, 2010, 2s: 144-149.
[38] Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo controlled clinical trial with a rho-kinase

inhibitor in pulmonary arterial hypertension. Circ J, 2013, 77: 2619-2625.
[39] Porvasnik SL, Germain S, Embury J, et al. PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces

monocrotaline- induced pulmonary arterial hypertension and right ventricular hypertrophy in rats. J Pharmacol Exp Ther,

2010, 334: 364-372.
[40] Dumitrascu R, Kulcke C, Konigshoff M, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in

rats. Eur Respir J, 2011, 37: 1104-1118.
[41] Zopf DA, das Neves LA, Nikula KJ, et al. C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents

monocrotaline-inducedpulmonary arterial hypertension in rats. Eur J Pharmacol, 2011, 670: 195-203.
[42] Kwapiszewska G, Markart P, Dahal BK, et al. PAR-2 Inhibition reverses experimental pulmonary hypertension. Circ Res,

2012, 110: 1179-1191.
[43] Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension:

results of the randomized IMPRES study. Circulation, 2013, 127: 1128-1138.
[44] Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll

Cardiol, 2013, 62: D60-72.
[45] Coeytaux RR, Schmit KM, Kraft B, et al. Comparative effectiveness and safety of drug therapy for pulmonary arterial

hypertension: a systematic review and meta-analysis. Chest, 2014, 145: 1055-1063.
[46] Lajoie AC, Lauzière G, Lega JC, et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a

meta-analysis. Lancet Respir Med, 2016, 4: 291-305.
[47] Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.

N Engl J Med, 2015, 373: 834-844.
[48] Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in

patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med, 2008, 149: 521-530.
[49] Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J

Med, 2013, 369: 330-340.
[50] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial

hypertension. N Engl J Med, 2013, 369: 809-818.
[51] McLaughlin V, Channick R, Ghofrani HA, et al. Effect of bosentan and sildenafil combination therapy on morbidity and

mortality in pulmonary arterial hypertension(PAH): results from the COMPASS-2 study. Chest, 2014, 146: 860A.
[52] Pfizer. Assess the efficacy and safety of sildenafil when added to bosentan in the treatment of pulmonary arterial

hypertension, 2014. https://clinicaltrials. gov/ct2/show/study/NCT00323297.
[53] Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J

Med, 2013, 369: 330-340.
[54] McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in

pulmonary arterial hypertension. Am J Respir Crit Care Med, 2006, 174: 1257-1263.
[55] McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial

hypertension: a randomized controlled clinical trial. J Am Coll Cardiol, 2010, 55: 1915-1922.
[56] Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in

patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy(the FREEDOM-C

study): a randomized controlled trial. Chest, 2012, 142: 1383-1390.
[57] Galie N, Muller K, Scalise AV, et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus

sildenafil in pulmonary arterial hypertension. Eur Respir J, 2015, 45: 1314-1122.

(编辑:张澜 收稿日期:2016-04-15)